X chromosome protects against bladder cancer in females via a<i>KDM6A</i>-dependent epigenetic mechanism

Kaneko, Satoshi; Li, Xue

doi:10.1126/sciadv.aar5598

Cited by 117 publications

(112 citation statements)

References 42 publications

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“…Finally, we examined sex bias with the BBN-induced orthotopic bladder cancer model. Consistent with earlier reports 12,13 , WT female mice survived longer after BBN exposure. However, Tcrb/Tcrd KO mice lacked sex differences in BBN-induced carcinogenesis ( Extended Data Fig.…”

Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murisupporting

confidence: 93%

“…In contrast to prior studies that have largely focused on sex differences in tumor cell intrinsic biology in the settings of bladder 13,34 and other cancers 35–40 , our work highlights the critical role of T cell immunity. We demonstrate that distinct CD8 + TIL fate determination underlies sex bias in spontaneous rejection of murine bladder tumor models, which provides a potential mechanism underlying sex differences in human bladder cancer incidence.…”

Section: Discussioncontrasting

confidence: 61%

“…C57BL/6 (WT; Stock number 000664), C57BL/6 Rag2 −/− (008449), Tcrb/Tcrd −/− (002122), Ighm −/− (002288) and FCG 13 (Four Core Genotype; 010905) mice were obtained from Jackson Labs. 5-12 weeks old mice, maintained in a specific pathogen-free environment, were used for experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Male bias in bladder cancer can be modeled successfully in mice with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced cancer 12,13 and a transplantable syngeneic bladder cancer cell line MB49 14 . To assess the contribution of adaptive immunity to sex bias, we compared MB49 growth in male and female wild type (WT) mice, as well as mice with a deficiency of T cells ( Tcrb/Tcrd −/− ), B cells ( Ighm −/− ) or both ( Rag2 −/− ).…”

Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murimentioning

confidence: 99%

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Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Kwon¹,

Chung²,

Kaneko³

et al. 2020

Preprint

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Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed. 24Abstract: Men and women show striking yet unexplained discrepancies in 25 incidence, clinical presentation, and therapeutic response across different types of 26 infectious/autoimmune diseases and malignancies 1,2 . For instance, bladder cancer 27 shows a 4-fold male-biased incidence that persists after adjustment for known risk 28 factors 3,4 . Here, we utilize murine bladder cancer models to establish that male-biased 29 tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex 30 differences exist in early fate decisions by intratumoral CD8 + T cells following their 31 activation. While female CD8 + T cells retain their effector function, male counterparts 32 readily adopt a Tcf1 low Tim3progenitor state that becomes exhausted over tumor 33 progression. Human cancers show an analogous male-biased frequency of exhausted 34 CD8 + T cells. Mechanistically, we describe an opposing interplay between CD8 + T cell 35 intrinsic androgen and type I interferon 5,6 signaling in Tcf1/Tcf7 regulation and formation 36 of the progenitor exhausted T cell subset. Consistent with female-biased interferon 37 response 7 , testosterone-dependent stimulation of Tcf1/Tcf7 and resistance to interferon 38 occurs to a greater magnitude in male CD8 + T cells. Male-biased predisposition for CD8 + 39T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder 40 tumors is less common in males and carries implications for therapeutic efficacy of 41 immune checkpoint inhibitors 8,9 . 42Main: Sex is a biological variable with significant influence on immune function 1 . 43However, mechanisms underlying sex-biased incidence and mortality of various cancers 44 arising in non-reproductive organs remain elusive 2 . Indeed, bladder cancer shows a 4-45 fold male-biased incidence globally, which cannot be explained by established risk 46 factors: smoking, exposure to occupational hazards and urinary tract infection 3,4 . Here, 48 largely mediated by sex differences in T cell immunity. Flow cytometric and single cell 49 RNA-seq analyses of CD8 + tumor-infiltrating leukocytes (TILs) identified a striking male 50 bias in the formation of Tcf1 low Tim3progenitor cells 10 and in their transition to a 51 hypofunctional Tcf1 -Tim3 + exhausted state upon prolonged stimulation. In particular, 52androgen signaling was enriched in the progenitor exhausted subset. We found that 53 testosterone-induced Tcf1, an early molecular orchestrator of an exhaustion-associated 54 transcriptional landscape 11 in male CD8 + T cells, is also more resistant to pertinent 55 repression by female-biased type I interferon signaling 5 . Collectively, these findings 56 highlight sex differences in intratumoral CD8 + T cell fate as a potential mechanism 57 underlying bladder cancer sex bias and identify androgen as a possible target to modulate 58 CD8 + TIL exhaustion. 59CD8 + T cell immunity is required for sex differences in murine...

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Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murisupporting

confidence: 93%

Section: Discussioncontrasting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Cd8+ T Cell Immunity Is Required For Sex Differences In Murimentioning

confidence: 99%

See 2 more Smart Citations

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Kwon¹,

Chung²,

Kaneko³

et al. 2020

Preprint

Self Cite

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“…Typically, only female mice are used for the MB49 mouse model as catheterization of male mice is reported to be unattainable by many preclinical bladder studies (El Behi et al, 2013;Hagberg et al, 1983;Oliveira et al, 2009;Olson et al, 2016;Seager et al, 2009). Given that more men than women develop bladder cancer, and that sex differences contribute to this bias in incidence (Kaneko and Li, 2018), we used a male mouse intravesical instillation protocol that we previously optimized to measure sex-specific differences in innate immunity to urinary tract infection (Zychlinsky Scharff et al, 2017;Zychlinsky Scharff et al, 2019). We implanted female and male mice with MB49 to determine whether sex differences impact immunity or response to BCG.…”

Section: Bcg Vaccination Increases Immune Cell Infiltration In Combinmentioning

confidence: 99%

Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Rousseau

O'Brien

Antequera

et al. 2020

Preprint

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Bladder cancer is the fourth most common cancer for men. However, women are often diagnosed with later stage disease and have poorer outcomes. Whether immune-based sex differences contribute to this discrepancy is unclear. In addition, models to investigate tumorspecific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking. To address this specific unmet need, we incorporated a commonly used model antigen, ovalbumin, into two well-established models of bladder cancer; the orthotopic MB49 cell line model and the carcinogenic BBN bladder cancer model. We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes. We found that BCG vaccination, prior to weekly BCG instillation does not impart an immune-specific benefit to tumor-bearing mice in the context of multiple BCG instillations.Furthermore, tumors developed in the testes in male mice, precluding the use of the MB49 model to directly investigate sex-based immune differences. In the BBN model, we observed that more tumor antigen-specific CD8 + T cells infiltrated male bladders compared to female bladders in the context of BCG immunotherapy and that these cells had the highest levels of the exhaustion marker PD-1. We propose our modified BBN model will contribute to our understanding of how tumor-specific immunity arises in bladder cancer. Additionally, the BBN bladder cancer model may help to uncover sex differences in tumor-specific immunity, which would provide valuable information for the development of new treatments or combination therapies for bladder cancer in women and men.

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Analysis of genetic profiling, pathomics signature, and prognostic features of primary lymphoepithelioma‐like carcinoma of the renal pelvis

et al. 2022

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carcinogenesis of primary LELC may be due to different genetic variations, including single-nucleotide variants, insertion and deletions, structural variations, and repeat regions, which may provide the basis for clinical diagnosis and treatment. The prognosis of LELC in the upper urinary tract is similar to that of UUT-UC. We suggest that the focal subtype can serve as a prognostic factor for LELC of the upper urinary tract; however, further studies are required to confirm this.

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X chromosome protects against bladder cancer in females via aKDM6A-dependent epigenetic mechanism

Abstract: Why are men more likely than women to have cancer? We report that the genetic inequality is an independent intrinsic cause.

Cited by 117 publications

References 42 publications

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Analysis of genetic profiling, pathomics signature, and prognostic features of primary lymphoepithelioma‐like carcinoma of the renal pelvis

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X chromosome protects against bladder cancer in females via aKDM6A-dependent epigenetic mechanism

Abstract: Why are men more likely than women to have cancer? We report that the genetic inequality is an independent intrinsic cause.

Cited by 117 publications

References 42 publications

Distinct CD8+T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Distinct CD8+T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Analysis of genetic profiling, pathomics signature, and prognostic features of primary lymphoepithelioma‐like carcinoma of the renal pelvis

Contact Info

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Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome